Herpes simplex viruses types 1 and 2 (HSV1, HSV2) and Varicella zoster virus (VZV) establish latent infections in nerve cells, and reactivation of virus causes recurrent disease at the original site of infection. Recurrent HSV and VZV infections represent serious sociomedical problems in which up to one half of infected individuals may have one or more episodes of clinical disease per year. Antiviral agents such as acyclovir are effective in suppressing the symptoms of the lytic phase of recurrent disease but are not able to abolish the latent infection or reduce the transmissibility of the infection. Among virally encoded enzymes implicated in reactivation, we have identified selective, nonsubstrate inhibitors of thymidine kinases (TK) and uracil-DNA glycosylase (UDG). A potent, water soluble TK inhibitor has been shown to block induced reactivation of HSV1 in a mouse model. We propose to synthesize derivatives of inhibitors of HSV1, HSV2 and VZV TKs, and of HSV1 UDG, for the purposes of studying the active and inhibitor binding sites of the enzymes and as potential drugs to prevent Herpesvirus recurrences. Specific aims include: 1, synthesis and structure-activity relationships of inhibitors of HSV1,HSV2 and VZV TK, i.e. N2-substituted guanines, and computer modelling of inhibitor:enzyme interactions; 2, synthesis and inhibitory properties of UDG inhibitors related to 6-(p-n- hexylanilino)uracil, including computer docking experiments with crystallographic structures of the enzyme; 3, synthesis, physiocochemical properties, and pharmacokinetic studies in mice of suitable TK and UDG inhibitors for testing in animal models of Herpesvirus reactivation. Certain .enzymatic assays and in vivo studies of viral reactivation will be done by collaborators.